The relationship of hereditary factors to the generation of common human cancers is of great scientific and public importance. In colorectal cancers, in particular, the debate about heredity and environment has gone on for almost a century. It is ironic that one of the earliest descriptions of an "inherited cancer" involved hereditary adenocarcinoma of the colon in a large family (A. S. Warthin, Arch. Intern. Med. 12, 546 (1913)). Yet eighty years later, there is still no proof that hereditary factors are primarily involved in such families. Part of the problem in establishing such proof is that colon cancer, like certain psychiatric disorders, are so common in, the general population that it is difficult to rule out chance clustering and other non-hereditary factors in such families. Moreover, the environment, notably diet, has been shown to play a significant role in colorectal cancer risk (B. Armstrong and R. Doll, Int. J. Cancer 15, 617 (1975); W. C. Willett and B. MacMahon, N. Engl. J. Med. 310, 697 (1984); Willett W., Nature 338, 389 (1989)). Members of an individual family are likely to share similar diets, further complicating definitive analysis.
We have attempted to gain evidence for a genetic component through linkage analysis. There are two major forms of colorectal cancer (CRC) predisposition that are currently recognized. The first, called familial adenomatous polyposis (FAP), is recognizable because affected patients have several unusual phenotypic features, particularly the presence of thousands of benign tumors lining the entire large intestine. FAP accounts for approximately 1% of colorectal cancer cases in the Western world (J. J. Mulvihill, in Prevention of Hereditary Large Bowel Cancer, J. R. Ingall and A. J. Mastromarino, Eds. Alan R. Liss, New York, 1983, pp. 61-75; H. J. Jarvinen, Gut 33, 357 (1992)) and the APC gene responsible for FAP has recently been identified (K. W. Kinzler et al., Science 253, 661 (1991); I. Nishisho et al., ibid, 665; J. Groden et al., Cell 66, 589 (1991); G. Joslyn et al., ibid 601). A second form of colorectal cancer which appears in familial patterns is called Hereditary Non-Polyposis Colorectal Cancer (HNPCC). It is more common than FAP, accounting for 5-13% of colorectal cancers in industrial nations (H. T. Lynch et al., Cancer 56, 939 (1985); J.-P. Mecklin, Gastroenterology 93, 1021 (1987); F. Kee and B. J. Collins, Gut 32, 509 (1991); J. R. Jass and S. M. Stewart, Gut 33, 783 (1992); R. S Houlston, A. Collins, J. Slack, N. E. Morton, Ann. Hum. Genet. 56, 99 (1992)). It is impossible to reliably distinguish individual patients with this form of CRC from "sporadic" cases on physical examination, as neither have diffuse polyposis or other unusual stigmata. A commonly used criterion for defining kindreds with HNPCC is that at least three relatives in two generations have colorectal cancer, one of the relatives diagnosed at less than 50 years of age (H. F. A. Vasen, J.-P. Mecklin, P. Meera Khan, H. T. Lynch, Dis. Colon Rectum 34, 424 (1991). In addition to the colon, other organs can be affected with cancer in HNPCC patients, including the endometrium, stomach, ovary, kidney; biliopancreatic system, and urinary tract (H. T. Lynch et al., Cancer Genet. Cytogenet. 53, 143 (1991); J. P. Mecklin and H. J. Jarvinen, Cancer 68, 1109 (1991)). Any individual with a family history of these cancers can be considered at risk for familial colon cancer, whether or not it conforms to the definition of HNPCC. Thus there is a need in the art for methods which will reliably distinguish hereditary (familial) from sporadic cases of colorectal cancer.